Network Of Transcription Factors Research Articles

Metal transport proteins and transcription factor networks in plant responses to cadmium stress.

Cadmium (Cd) contamination poses a significant threat to agriculture and human health due to its high soil mobility and toxicity. This review synthesizes current knowledge on Cd uptake, transport, detoxification, and transcriptional regulation in plants, emphasizing the roles of metal transport proteins and transcription factors (TFs). We explore transporter families like NRAMP, HMA, ZIP, ABC, and YSL in facilitating Cd movement within plant tissues, identifying potential targets for reducing Cd accumulation in crops. Additionally, regulatory TF families, including WRKY, MYB, bHLH, and ERF, are highlighted for their roles in modulating gene expression to counteract Cd toxicity. This review consolidates the existing literature on plant-Cd interactions, providing insights into established mechanisms and identifying gaps for future research. Understanding these mechanisms is crucial for developing strategies to enhance plant tolerance, ensure food safety, and promote sustainable agriculture amidst increasing heavy-metal pollution.

Transcription factor 4 is a key mediator of oncogenesis in neuroblastoma by promoting MYC activity.

Super-enhancer-associated transcription factor networks define cell identity in neuroblastoma (NB). Dysregulation of these transcription factors contributes to the initiation and maintenance of NB by enforcing early developmental identity states. We report that the class I basic helix-loop-helix (bHLH) transcription factor 4 (TCF4; also known as E2-2) is a critical NB dependency gene that significantly contributes to these identity states through heterodimerization with cell-identity-specific bHLH transcription factors. Knockdown of TCF4 significantly induces apoptosis in vitro and inhibits tumorigenicity in vivo. We used genome-wide expression profiling, TCF4 chromatin immunoprecipitation sequencing (ChIP-seq) and TCF4 immunoprecipitation-mass spectrometry to determine the role of TCF4 in NB cells. Our results, along with recent findings in NB for the transcription factors T-box transcription factor TBX2, heart- and neural crest derivatives-expressed protein 2 (HAND2) and twist-related protein 1 (TWIST1), propose a role for TCF4 in regulating forkhead box protein M1 (FOXM1)/transcription factor E2F-driven gene regulatory networks that control cell cycle progression in cooperation with N-myc proto-oncogene protein (MYCN), TBX2, and the TCF4 dimerization partners HAND2 and TWIST1. Collectively, we showed that TCF4 promotes cell proliferation through direct transcriptional regulation of the c-MYC/MYCN oncogenic program that drives high-risk NB. Mechanistically, our data suggest the novel finding that TCF4 acts to support MYC activity by recruiting multiple factors known to regulate MYC function to sites of colocalization between critical NB transcription factors, TCF4 and MYC oncoproteins. Many of the TCF4-recruited factors are druggable, giving insight into potential therapies for high-risk NB. This study identifies a new function for class I bHLH transcription factors (e.g., TCF3, TCF4, and TCF12) that are important in cancer and development.

Transcriptional and epigenetic characterization of a new in vitro platform to model the formation of human pharyngeal endoderm

BackgroundThe Pharyngeal Endoderm (PE) is an extremely relevant developmental tissue, serving as the progenitor for the esophagus, parathyroids, thyroids, lungs, and thymus. While several studies have highlighted the importance of PE cells, a detailed transcriptional and epigenetic characterization of this important developmental stage is still missing, especially in humans, due to technical and ethical constraints pertaining to its early formation.ResultsHere we fill this knowledge gap by developing an in vitro protocol for the derivation of PE-like cells from human Embryonic Stem Cells (hESCs) and by providing an integrated multi-omics characterization. Our PE-like cells robustly express PE markers and are transcriptionally homogenous and similar to in vivo mouse PE cells. In addition, we define their epigenetic landscape and dynamic changes in response to Retinoic Acid by combining ATAC-Seq and ChIP-Seq of histone modifications. The integration of multiple high-throughput datasets leads to the identification of new putative regulatory regions and to the inference of a Retinoic Acid-centered transcription factor network orchestrating the development of PE-like cells.ConclusionsBy combining hESCs differentiation with computational genomics, our work reveals the epigenetic dynamics that occur during human PE differentiation, providing a solid resource and foundation for research focused on the development of PE derivatives and the modeling of their developmental defects in genetic syndromes.

Sequences within and upstream of the mouse Ets1 gene drive high level expression in B cells, but are not sufficient for consistent expression in T cells.

The levels of transcription factor Ets1 are high in resting B and T cells, but are downregulated by signaling through antigen receptors and Toll-like receptors (TLRs). Loss of Ets1 in mice leads to excessive immune cell activation and development of an autoimmune syndrome and reduced Ets1 expression has been observed in human PBMCs in the context of autoimmune diseases. In B cells, Ets1 serves to prevent premature activation and differentiation to antibody-secreting cells. Given these important roles for Ets1 in the immune response, stringent control of Ets1 gene expression levels is required for homeostasis. However, the genetic regulatory elements that control expression of the Ets1 gene remain relatively unknown. Here we identify a topologically-associating domain (TAD) in the chromatin of B cells that includes the mouse Ets1 gene locus and describe an interaction hub that extends over 100 kb upstream and into the gene body. Additionally, we compile epigenetic datasets to find several putative regulatory elements within the interaction hub by identifying regions of high DNA accessibility and enrichment of active enhancer histone marks. Using reporter constructs, we determine that DNA sequences within this interaction hub are sufficient to direct reporter gene expression in lymphoid tissues of transgenic mice. Further analysis indicates that the reporter construct drives faithful expression of the reporter gene in mouse B cells, but variegated expression in T cells, suggesting the existence of T cell regulatory elements outside this region. To investigate how the downregulation of Ets1 transcription is associated with alterations in the epigenetic landscape of stimulated B cells, we performed ATAC-seq in resting and BCR-stimulated primary B cells and identified four regions within and upstream of the Ets1 locus that undergo changes in chromatin accessibility that correlate to Ets1 gene expression. Interestingly, functional analysis of several putative Ets1 regulatory elements using luciferase constructs suggested a high level of functional redundancy. Taken together our studies reveal a complex network of regulatory elements and transcription factors that coordinate the B cell-specific expression of Ets1.

Hierarchical lncRNA regulatory network in early-onset severe preeclampsia

BackgroundRecent studies have shown that several long non-coding RNAs (lncRNAs) in the placenta are associated with preeclampsia (PE). However, the extent to which lncRNAs may contribute to the pathological progression of PE is unclear.ResultsHere, we report a hierarchical regulatory network involved in early-onset severe PE (EOSPE). We have carried out transcriptome sequencing on the placentae from patients and normal subjects to identify the differentially expressed genes (DEGs), including some lncRNAs (DElncRNAs). We then constructed a high-quality hierarchical regulatory network of lncRNAs, transcription factors (TFs), and target DEGs, containing 1851 lncRNA-TF interactions and 6901 TF-promoter interactions. The lncRNA-to-target regulatory interactions were further validated by the triplex structures between the DElncRNAs and the promoters of the target DEGs. The DElncRNAs in the regulatory network were clustered into 3 clusters, one containing DElncRNAs correlated with the blood pressure, including FLNB-AS1 with targeting 27.89% (869/3116) DEGs in EOSPE. We further demonstrated that FLNB-AS1 could bind the transcription factor JUNB to regulate a series members of the HIF-1 signaling pathway in trophoblast cells.ConclusionsOur results suggest that the differential expression of lncRNAs may perturb the lncRNA-TF-DEG hierarchical regulatory network, leading to the dysregulation of many genes involved in EOSPE. Our study provides a new strategy and a valuable resource for studying the mechanism underlying gene dysregulation in EOSPE patients.

Necroptosis in recurrent implantation failure: A bioinformatics analysis of key genes and therapeutic targets.

Recurrent implantation failure (RIF), a major issue in assisted reproductive technology (ART), may be influenced by necroptosis, a form of cell death linked to several diseases. This study was aimed at investigating the involvement of necroptosis in RIF. Using RNA-sequencing data from the Gene Expression Omnibus database, we identified differentially expressed necroptosis-related genes (DENRGs) in RIF patients compared with those in controls. Functional enrichment, protein-protein interaction (PPI) networks, and transcription factor (TF) regulatory networks were analyzed to identify key genes. Immune cell infiltration was analyzed using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Finally, potential therapeutic drugs targeting key genes were explored using a Drug Gene Interaction Database. In total, 20 DENRGs associated with RIF were identified, with a focus on 6 key genes (MLKL, FASLG, XIAP, CASP1, BIRC3, and TLR3) implicated in necroptosis and immune processes. These genes were used to develop a predictive model for RIF, which was validated in 2 datasets. The model and TF network analysis underscored the importance of TLR3. Immune infiltration analysis showed reduced levels of 16 immune cells in RIF patients, highlighting immune system alterations. Several drugs targeting CASP1, such as nivocasan and emricasan, were identified as potential treatments. The study sheds light on the role of necroptosis in RIF, identifying key genes and immune alterations that could serve as biomarkers and therapeutic targets. These findings pave the way for future experimental research and clinical applications targeting necroptosis in RIF treatment.

Prostate cancers with distinct transcriptional programs in Black and White men

BackgroundBlack men are at a higher risk of prostate cancer (PC) diagnosis and present with more high-grade PC than White men in an equal access setting. This study aimed to identify differential transcriptional regulation between Black and White men with PC.MethodsWe performed microarray of radical prostatectomy tissue blocks from 305 Black and 238 White men treated at the Durham Veterans Affairs Medical Center. Differential expression, gene set enrichment analysis, master regulator analysis, and network modeling were conducted to compare gene expression by race. Findings were validated using external datasets that are available in the Gene Expression Omnibus (GEO) database. The first was a multi-institutional cohort of 1152 prostate cancer patients (596 Black, 556 White) with microarray data (GEO ID: GSE169038). The second was an Emory cohort of 106 patients (22 Black, 48 White, 36 men of unknown race) with RNA-seq data (GEO ID: GSE54460). Additionally, we analyzed androgen receptor (AR) chromatin binding profiles using paired AR ChIP-Seq datasets from Black and White men (GEO IDs: GSE18440 and GSE18441).ResultsWe identified 871 differentially expressed genes between Black and White men. White men had higher activity of MYC-related pathways, while Black men showed increased activity of inflammation, steroid hormone responses, and cancer progression-related pathways. We further identified the top 10 transcription factors (TFs) in Black patients, which formed a transcriptional regulatory network centered on the AR. The activities of this network and the pathways were significantly different in Black vs. White men across multiple cohorts and PC molecular subtypes.ConclusionsThese findings suggest PC in Black and White men have distinct tumor transcriptional profiles. Furthermore, a highly interactive TF network centered on AR drives differential gene expression in Black men. Additional study is needed to understand the degree to which these differences in transcriptional regulatory elements contribute to PC health disparities.

LAFL Factors in Seed Development and Phase Transitions.

Development is a chain reaction in which one event leads to another until the completion of a life cycle. Phase transitions are milestone events in the cycle of life. LEAFY COTYLEDON1 (LEC1), ABA INSENSITIVE3 (ABI3), FUSCA3 (FUS3), and LEC2 proteins, collectively known as LAFL, are master transcription factors (TFs) regulating seed and other developmental processes. Since the initial characterization of the LAFL genes, more than three decades of active research has generated tremendous amounts of knowledge about these TFs, whose roles in seed development and germination have been comprehensively reviewed. Recent advances in cell biology with genetic and genomic tools have allowed the characterization of the LAFL regulatory networks in previously challenging tissues at a higher throughput and resolution in reference species and crops. In this review, we provide a holistic perspective by integrating advances at the epigenetic, transcriptional, posttranscriptional, and protein levels to exemplify the spatiotemporal regulation of the LAFL networks in Arabidopsis seed development and phase transitions, and we briefly discuss the evolution of these TF networks.

Transcription factor network dynamics during the commitment to oncogene-induced senescence

Aberrant oncogenic signaling causes cells to transition into oncogene-induced senescence (OIS) to limit uncontrolled proliferation. Despite being a potent tumor suppressor mechanism, OIS is an unstable cell state susceptible to reprogramming that can promote tumorigenesis. Therefore, elucidating the underlying gene regulatory mechanisms that commit cells to OIS is critical to identifying actionable targets to modulate the senescence state. We previously showed that timely execution of the OIS program is governed by hierarchical transcription factor (TF) networks. However, the gene regulatory mechanisms that prime cells to commit to the OIS fate early upon oncogene hyperactivation are currently not known. Here, we leveraged our time-resolved multi-omic profiling approach to generate TF networks during the first 24 h of oncogenic HRASG12V activation. Using this approach, we demonstrate that the commitment to OIS requires the rearrangement of the TF network on a pre-established epigenomic landscape, priming the cells for the substantial chromatin remodeling that underpins the transition to OIS. Our results provide a detailed map of the chromatin landscape before cells transition to OIS thus offering a platform for manipulation of senescence outcomes of potentially therapeutic value.

Identification of Potential Biomarkers for Patients with DWI-Negative Ischemic Stroke

Ischemic stroke is the leading cause of long-term disability in adults, accounting for 80% of stroke cases. Diffusion weighted imaging (DWI) examination is the main test for acute ischemic stroke, but in recent years, several studies have shown that some patients show negative DWI examination after the onset of ischemic stroke with symptoms of significant neurological deficits. In this study, we investigated potential biomarkers related to immune metabolism in the peripheral blood of DWI-negative versus DWI-positive patients after ischemic stroke and explored their possible regulatory processes in ischemic stroke. The datasets related to ischemic stroke were downloaded from the GEO database, immune-related genes and metabolism-related genes were obtained from the ImmPort database and MSigDB database, respectively, and immune-related differential genes were obtained based on immune scores using the algorithm of the R software package “GSVA.” Candidate genes were selected based on intersections, hub genes were screened using the algorithm in Cytoscape software, and finally, GeneMANIA analysis, GSEA enrichment analysis, subcellular localization, gene transcription factor and gene-drug interaction networks, and disease correlation analyses were performed for the hub genes. Five hub genes (GART, TYMS, PPAT, CTPS1, and PAICS) were obtained by PPI network analysis and software analysis. Among them, PPAT and PAICS may be the real hub genes with consistent and significantly differentiated results from the discovery and validation sets. The functions of these hub genes may be related to pathways such as nucleotide biosynthetic processes. The constructed hub gene ceRNA network showed that hsa-10a-5p is the key miRNA connecting PAICS and multiple lncRNAs in this study. Differential genes related to immunity and metabolism in DWI-negative and DWI-positive patients after IS were identified using bioinformatics analysis, and their pathways and related TF-RNAs, miRNAs, and lncRNAs were identified. These genes may be considered effective targets for the diagnosis and treatment of ischemic stroke.

CilioGenics: an integrated method and database for predicting novel ciliary genes.

Uncovering the full list of human ciliary genes holds enormous promise for the diagnosis of cilia-related human diseases, collectively known as ciliopathies. Currently, genetic diagnoses of many ciliopathies remain incomplete (1-3). While various independent approaches theoretically have the potential to reveal the entire list of ciliary genes, approximately 30% of the genes on the ciliary gene list still stand as ciliary candidates (4,5). These methods, however, have mainly relied on a single strategy to uncover ciliary candidate genes, making the categorization challenging due to variations in quality and distinct capabilities demonstrated by different methodologies. Here, we develop a method called CilioGenics that combines several methodologies (single-cell RNA sequencing, protein-protein interactions (PPIs), comparative genomics, transcription factor (TF) network analysis, and text mining) to predict the ciliary capacity of each human gene. Our combined approach provides a CilioGenics score for every human gene that represents the probability that it will become a ciliary gene. Compared to methods that rely on a single method, CilioGenics performs better in its capacity to predict ciliary genes. Our top 500 gene list includes 258 new ciliary candidates, with 31 validated experimentally by us and others. Users may explore the whole list of human genes and CilioGenics scores on the CilioGenics database (https://ciliogenics.com/).

Body-Wide Inactivation of the Myc-Like Mlx Transcription Factor Network Accelerates Aging and Increases the Lifetime Cancer Incidence.

The "Mlx" and "Myc" transcription factor networks cross-communicate and share many common gene targets. Myc's activity depends upon its heterodimerization with Max, whereas the Mlx Network requires that the Max-like factor Mlx associate with the Myc-like factors MondoA or ChREBP. The current work demonstrates that body-wide Mlx inactivation, like that of Myc, accelerates numerous aging-related phenotypes pertaining to body habitus and metabolism. The deregulation of numerous aging-related Myc target gene sets is also accelerated. Among other functions, these gene sets often regulate ribosomal and mitochondrial structure and function, genomic stability, and aging. Whereas "MycKO" mice have an extended lifespan because of a lower cancer incidence, "MlxKO" mice have normal lifespans and a higher cancer incidence. Like Myc, the expression of Mlx, MondoA, and ChREBP and their control over their target genes deteriorate with age in both mice and humans. Collectively, these findings underscore the importance of lifelong and balanced cross-talk between the two networks to maintain proper function and regulation of the many factors that can affect normal aging.

Lineage-dependence of the neuroblastoma surfaceome defines tumor cell state-dependent and independent immunotherapeutic targets.

Neuroblastoma is a heterogeneous disease with adrenergic (ADRN)- and therapy resistant mesenchymal (MES)-like cells driven by distinct transcription factor networks. Here, we investigate the expression of immunotherapeutic targets in each neuroblastoma subtype and propose pan-neuroblastoma and cell state specific targetable cell-surface proteins. We characterized cell lines, patient-derived xenografts, and patient samples as ADRN-dominant or MES- dominant to define subtype-specific and pan-neuroblastoma gene sets. Targets were validated with ChIP- sequencing, immunoblotting, and flow cytometry in neuroblastoma cell lines and isogenic ADRN-to-MES transition cell line models. Finally, we evaluated the activity of MES-specific agents in vivo and in vitro . Most immunotherapeutic targets being developed for neuroblastoma showed significantly higher expression in the ADRN subtype with limited expression in MES-like tumor cells. In contrast, CD276 (B7-H3) and L1CAM maintained expression across both ADRN and MES states. We identified several receptor tyrosine kinases (RTKs) enriched in MES-dominant samples and showed that AXL targeting with ADCT-601 was potently cytotoxic in MES-dominant cell lines and showed specific anti-tumor activity in a MES cell line-derived xenograft. Immunotherapeutic strategies for neuroblastoma must address the potential of epigenetic downregulation of antigen density as a mechanism for immune evasion. We identified several RTKs as candidate MES-specific immunotherapeutic target proteins for the elimination of therapy-resistant cells. We hypothesize that the phenomena of immune escape will be less likely when targeting pan-neuroblastoma cell surface proteins such as B7-H3 and L1CAM, and/or dual targeting strategies that consider both the ADRN- and MES-cell states. Cellular plasticity influences the abundance of immunotherapeutic targets.Subtype-specific targets may be susceptible to epigenetically-mediated downregulation.Immunotherapeutic targets in development, B7-H3 and L1CAM, show "pan-subtype" expression. Neuroblastoma is a lethal childhood malignancy that shows cellular plasticity in response to anti-cancer therapies. Several plasma membrane proteins are being developed as immunotherapeutic targets in this disease. Here we define which cell surface proteins are susceptible to epigenetically regulated downregulation during an adrenergic to mesenchymal cell state switch and propose immunotherapeutic strategies to anticipate and circumvent acquired immunotherapeutic resistance.

Bioinformatics analysis of the association between obesity and gastric cancer.

Obesity and gastric cancer (GC) are prevalent diseases worldwide. In particular, the number of patients with obesity is increasing annually, while the incidence and mortality rates of GC are ranked high. Consequently, these conditions seriously affect the quality of life of individuals. While evidence suggests a strong association between these two conditions, the underlying mechanisms of this comorbidity remain unclear. We obtained the gene expression profiles of GSE94752 and GSE54129 from the Gene Expression Omnibus database. To investigate the associated biological processes, pathway enrichment analyses were conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes for the shared differentially expressed genes in obesity and GC. A protein-protein interaction (PPI) network was subsequently established based on the Search Tool for the Retrieval of Interacting Genes (STRING) database, followed by the screening of the core modules and central genes in this network using Cytoscape plug-in MCODE. Furthermore, we scrutinized the co-expression network and the interplay network of transcription factors (TFs), miRNAs, and mRNAs linked to these central genes. Finally, we conducted further analyses using different datasets to validate the significance of the hub genes. A total of 246 shared differentially expressed genes (209 upregulated and 37 downregulated) were selected for ensuing analyses. Functional analysis emphasized the pivotal role of inflammation and immune-associated pathways in these two diseases. Using the Cytoscape plug-in CytoHubba, nine hub genes were identified, namely, CXCR4, CXCL8, CXCL10, IL6, TNF, CCL4, CXCL2, CD4, and CCL2. IL6 and CCL4 were confirmed as the final hub genes through validation using different datasets. The TF-miRNA-mRNA regulatory network showed that the TFs primarily associated with the hub genes included RELA and NFKB1, while the predominantly associated miRNAs included has-miR-195-5p and has-miR-106a-5p. Using bioinformatics methods, we identified two hub genes from the Gene Expression Omnibus datasets for obesity and GC. In addition, we constructed a network of hub genes, TFs, and miRNAs, and identified the major related TFs and miRNAs. These factors may be involved in the common molecular mechanisms of obesity and GC.

A common gene signature of the right ventricle in failing rat and human hearts

The molecular mechanisms of progressive right heart failure are incompletely understood. In this study, we systematically examined transcriptomic changes occurring over months in isolated cardiomyocytes or whole heart tissues from failing right and left ventricles in rat models of pulmonary artery banding (PAB) or aortic banding (AOB). Detailed bioinformatics analyses resulted in the identification of gene signature, protein and transcription factor networks specific to ventricles and compensated or decompensated disease states. Proteomic and RNA-FISH analyses confirmed PAB-mediated regulation of key genes and revealed spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with transcriptome datasets from human patients with chronic thromboembolic pulmonary hypertension (CTEPH) led to the identification of more than 50 genes whose expression levels correlated with the severity of right heart disease, including multiple matrix-regulating and secreted factors. These data define a conserved, differentially regulated genetic network associated with right heart failure in rats and humans.

Integrative Analysis of Transcriptional Regulation of the ATG4D, an Autophagy-Related Gene, Using JASPAR and STRING databases.

Autophagy is a catabolic cellular process that is conserved and plays an important role in sustaining cellular stability, adjusting to malnourishment, and responding to cellular stress. ATG4D is a gene that involves the formation of the autophagosome and is considered a key player in autophagy. Inclusive knowledge of how the ATG4D gene is regulated may provide insights into the gene's role in different cellular aspects. In this research, bioinformatics tools were utilized, specifically the JASPAR database, to predict the transcription factor binding sites (TFBS) and transcription factors (TFs) binding to the ATG4D promoter region. Multiple TFs were identified, and among these identified TFs, we focused on eight that were well-known for their established roles in regulating autophagy, responding to cellular stress, and promoting transcriptional regulation of ATG4D. These TFs include FOXO3, TFEB, TP53, SP1, STAT3, NF-κB, E2F1, and CREB1. To discover the functional interactions of these TFs, the STRING database was utilized to conduct protein-protein interaction analysis and functional enrichment. This analysis helped us to better comprehend the complicated regulatory network linked to autophagy and the precise role of ATG4D. Functional enrichment analysis revealed significant gene ontology terms and pathways linked with autophagy, cellular stress response, apoptosis, and transcriptional regulation. These findings indicate that the regulation of ATG4D gene expression is shaped by a complicated network of transcription factors that play significant roles in autophagy and sustaining cellular balance. Using a combination of bioinformatics tools such as JASPAR and STRING gave a thorough insight into the regulatory atmosphere of ATG4D, providing opportunities for treating diseases associated with autophagy dysregulation.

Transcription Factor Activity Regulating Macrophage Heterogeneity during Skin Wound Healing.

Monocytes and macrophages (Mos/Mϕs) play diverse roles in wound healing by adopting a spectrum of functional phenotypes; however, the regulation of such heterogeneity remains poorly defined. We enhanced our previously published Bayesian inference TF activity model, incorporating both single-cell RNA sequencing and single-cell ATAC sequencing data to infer transcription factor (TF) activity in Mos/Mϕs during skin wound healing. We found that wound Mos/Mϕs clustered into early-stage Mos/Mϕs, late-stage Mϕs, and APCs, and that each cluster showed differential chromatin accessibility and differential predicted TF activity that did not always correlate with mRNA or protein expression. Network analysis revealed two highly connected large communities involving a total of 19 TFs, highlighting TF cooperation in regulating wound Mos/Mϕs. This analysis also revealed a small community populated by NR4A1 and NFKB1, supporting a proinflammatory link between these TFs. Importantly, we validated a proinflammatory role for NR4A1 activity during wound healing, showing that Nr4a1 knockout mice exhibit decreased inflammatory gene expression in early-stage wound Mos/Mϕs, along with delayed wound re-epithelialization and impaired granulation tissue formation. In summary, our study provides insight into TF activity that regulates Mo/Mϕ heterogeneity during wound healing and provides a rational basis for targeting Mo/Mϕ TF networks to alter phenotypes and improve healing.

Cardiac Development Long Non-Coding RNA (CARDEL) Is Activated during Human Heart Development and Contributes to Cardiac Specification and Homeostasis.

Successful heart development depends on the careful orchestration of a network of transcription factors and signaling pathways. In recent years, in vitro cardiac differentiation using human pluripotent stem cells (hPSCs) has been used to uncover the intricate gene-network regulation involved in the proper formation and function of the human heart. Here, we searched for uncharacterized cardiac-development genes by combining a temporal evaluation of human cardiac specification in vitro with an analysis of gene expression in fetal and adult heart tissue. We discovered that CARDEL (CARdiac DEvelopment Long non-coding RNA; LINC00890; SERTM2) expression coincides with the commitment to the cardiac lineage. CARDEL knockout hPSCs differentiated poorly into cardiac cells, and hPSC-derived cardiomyocytes showed faster beating rates after controlled overexpression of CARDEL during differentiation. Altogether, we provide physiological and molecular evidence that CARDEL expression contributes to sculpting the cardiac program during cell-fate commitment.

Regulatory network analysis based on integrated miRNA-TF reveals key genes in heart failure

The etiology and pathophysiology of heart failure are still unknown. Increasing evidence suggests that abnormal microRNAs (miRNAs) and transcription factors (TFs) expression may be associated with the development of heart failure. Therefore, this study aims to explore key miRNAs, TFs, and related genes in heart failure to gain a greater understanding of the pathogenesis of heart failure. To search and download the dataset of mRNA chips related to heart failure from the GEO database (GSE59867, GSE9128, and GSE134766), we analyzed differential genes and screened the common differentially expressed genes on two chips using R language software. The binary interactions and circuits among miRNAs, TFs, and corresponding genes were determined by Pearson correlation coefficient. A regulatory network of miRNAs, TFs, and target genes was constructed based on bioinformatics. By comparing the sequences of patients with and without heart failure, five downregulated genes with hypermethylated mRNA and three upregulated genes with hypomethylated mRNA were identified. The miRNA-TF gene regulatory network consisted of 26 miRNAs, 22 TFs and six genes. GO and KEGG analysis results revealed that BP terms like cellular response to organic substance, cellular response to cytokine stimulus, and KEGG pathways like osteoclast differentiation, MAPK signaling pathway, and legionellosis were enriched of the DEGs. TMEM87A, PPP2R2A, DUSP1, and miR-92a have great potential as biomarkers for heart failure. The integrated analysis of the mRNA expression spectrum and microRNA-transcription factor-gene revealed the regulatory network of heart failure, which may provide clues to its alternative treatment.

Application of angiogenesis-related genes associated with immune infiltration in the molecular typing and diagnosis of acute myocardial infarction.

Angiogenesis has been discovered to be a critical factor in developing tumors and ischemic diseases. However, the role of angiogenesis-related genes (ARGs) in acute myocardial infarction (AMI) remains unclear. The GSE66360 dataset was used as the training cohort, and the GSE48060 dataset was used as the external validation cohort. The random forest (RF) algorithm was used to identify the signature genes. Consensus clustering analysis was used to identify robust molecular clusters associated with angiogenesis. The ssGSEA was used to analyze the correlation between ARGs and immune cell infiltration. In addition, we constructed miRNA-gene, transcription factor network, and targeted drug network of signature genes. RT-qPCR was used to verify the expression levels of signature genes. Seven signature ARGs were identified based on the RF algorithm. Receiver operating characteristic curves confirmed the classification accuracy of the risk predictive model based on signature ARGs (area under the curve [AUC] = 0.9596 in the training cohort and AUC = 0.7773 in the external validation cohort). Subsequently, the ARG clusters were identified by consensus clustering. Cluster B had a more generalized high expression of ARGs and was significantly associated with immune infiltration. The miRNA and transcription factor network provided new ideas for finding potential upstream targets and biomarkers. Finally, the results of RT-qPCR were consistent with the bioinformatics analysis, further validating our results. Angiogenesis is closely related to AMI, and characterizing the angiogenic features of patients with AMI can help to risk-stratify patients and provide personalized treatment.